People living with HIV (PLWH) have an increased life expectancy due to effective therapies. This has resulted in an increased incidence of non-AIDS defining cancers (NADCs), in particular, cancers caused by human papillomavirus (HPV). The most rapidly increasing HPV-related malignancy in the general US population is HPV-driven oropharyngeal cancer (HPV-OPC), a type of head and neck that has increased in incidence by more than 200% over the past few decades.1, 2 PLWH are 1.5 to 4 times more likely to develop HPV-OPC than the general population.3 They are also more likely to develop HPV-OPC at younger ages (51 versus 60)4 and have a less favorable cancer prognoses.5 Unlike cervical cancer, where the introduction of highly effective screening has significantly reduced the incidence and mortality of cervical cancer, there are no methods for early detection of HPV-OPC. A major barrier for early detection has been the inability to identify PLWH at highest risk for HPV-OPC given that a precancerous precursor lesion for OPC has yet to be identified. Recently, HPV16 E6 antibody positivity has been identified as a promising early biomarker. Previous work from our group showed that HPV16 E6 antibodies are present in up to 90% of HPV-OPC patients6 and appear more than 10 years prior to diagnosis.7-9 Additionally, we have shown that HPV16 E6 antibodies are highly specific for HPV-OPC10 and are not strongly associated with the 5 other cancers caused by HPV.11 The objective of this study is to evaluate the ability of the HPV16 E6 marker to identify a sub-population of PLWH at highest risk for developing HPV-OPC and for which head and neck cancer screening would be most effective. To accomplish this, we will conduct a natural history study of the HPV16 E6 antibody marker. This study will focus on men aged 40+ living with HIV given that ~85% of HPV-OPC cases occur in middle aged men and HIV infection additionally elevates risk by up to 4-fold. Using the Tennessee Center for AIDS Research (TN-CFAR) Biorepository, banked blood samples from men aged 40+ living with HIV (N=3,261) will be tested for HPV16 E6 antibodies. All HPV16 E6 seropositives and a subset of HPV16 E6 seronegatives (1:2 ratio) will be invited to participate in yearly (4 total) comprehensive head and neck cancer screening exams performed by a Vanderbilt Ingram Cancer Center (VICC) head and neck surgeon. Cancer screening visits will include: visual inspection of the mouth and palpation of tonsils, ultrasound imaging, laryngoscope exam, a detailed questionnaire and biospecimen collection. E6 seropositive men will be compared to E6 seronegative men in terms of: a) markers of elevated HPV-OPC risk and b) development of HPV-OPC. The specific aims are: (1) Estimate the prevalence of HPV16 E6 antibodies among men aged 40+ living with HIV; (2) Determine the association between HPV16 E6 seropositivity and markers of HPV-OPC risk; (3) Estimate the risk of developing: a) precancerous markers of HPV-OPC and/or; b) HPV-OPC by HPV16 E6 serostatus. We hypothesize that men with HPV16 E6 antibodies will be more likely to have known risk factors associated with HPV-OPC development [sexual behavior, persistent oral HPV infection] and will be more likely to develop HPV-OPC than men without HPV16 E6 antibodies. These efforts could help to generate evidence for oral health screening guidelines tailored to PLWH. This work is particularly impactful given that HPV-OPC disproportionately affects PLWH.